2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

B is pyridyl;

wherein B is unsubstituted or substituted by 1 to 3 R 3 moieties, wherein each R 3 moiety is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, C 1 -C 3 hydroxyalkyl, halo, hydroxy, amino, (C 1 -C 3 alkyl)amino, di(C 1 -C 3 alkyl)amino, —N(H)SO 2 —(C 1 -C 3 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(H)(C 1 -C 3 alkyl) 2 , —CH 2 O—(C 1 -C 4 alkylene)-OH, and E;

E is

(a) -E′,

(b) —CH 2 -E 1 or

(c) —O—CH 2 -E 1 ;

wherein E 1 is:

(i) phenyl; or

(ii) C 3 -C 6 cycloalkyl;

wherein E 1 is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, hydroxy, nitro, carboxy, C 1 -C 3 hydroxyalkyl, —O—(C 1 -C 3 fluoroalkyl), —C(H)(OH)—(C 1 -C 3 fluoroalkyl), —N(CH 3 )SO 2 —(C 1 -C 3 alkyl), and R E1 ;

wherein R E1 is

(a) —(CH 2 ) x —R E1a , wherein x is 1, 2, or 3; or

(b) —R E1a ;

wherein R E1a is

 phenyl;

 wherein R E1a is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy and halo;

A is selected from the group consisting of

(a)

 wherein

Y is —CH—;

R 11 and R 12 are independently H or F; and

n is 1 or 2;

n′ is 0 or 1; or

(b)

 wherein

R a and R b are independently H, C 1 -C 6 alkyl, or phenyl;

or R a and R b together with the carbon atom to which they are attached form —C(O)—;

Q is

 —C(O)—, or —CH 2 CH 2 —;

wherein R c is H, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, —(CH 2 ) r OR 13 , —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —(CH 2 ) r S(O) t R 14 , —(CH 2 ) r -phenyl, or —(CH 2 ) r N(H)C(O)—(C 1 -C 3 alkyl);

R 13 is H or C 1 -C 3 alkyl; and

R 14 is C 1 -C 3 alkyl;

r is 1 or 2;

t is 0, 1, or 2;

R d is H or C 1 -C 6 alkyl, or

R c and R d together with the carbon atom to which they are attached form a group of the formula

 wherein q is 1, 2, 3, or 4; or

(c)

 wherein m is 1 or 2 and m′ is 0 or 1;

(e) H;

(f) —C(O)N(H)—(C 1 -C 3 alkyl); and

(g) —S(O) 2 CH 2 CH 2 NH 2 .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

wherein said B is unsubstituted or substituted by 1 to 2 R 3 moieties.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is substituted by no more than 2 R 3 moieties, and no more than 1 of said R 3 moieties is E.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof,

A is

Y is —CH 2 —;

R 11 and R 12 are independently H or F; and

n is 1 or 2;

n′ is 0 or 1.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is

wherein R a and R b are independently H, C 1 -C 6 alkyl, or phenyl;

or R a and R b together with the carbon atom to which they are attached form —C(O)—;

Q

 is —C(O)—, or —CH 2 CH 2 —;

wherein R c is H, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, —(CH 2 ) r OR 13 , —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —(CH 2 ) r S(O) t R 14 , —(CH 2 ) r -phenyl, or —(CH 2 ) r N(H)C(O)—(C 1 -C 3 alkyl);

R 13 is H or C 1 -C 3 alkyl; and

R 14 is C 1 -C 3 alkyl;

r is 1 or 2;

t is 0, 1, or 2;

R d is H or C 1 -C 6 alkyl; or

R c and R d together with the carbon atom to which they are attached form a group of the formula

 wherein q is 1, 2, 3, or 4.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein

R a and R b are independently H or C 1 -C 4 alkyl;

Q is —C(O)— or

R c is H, C 1 -C 4 alkyl, cyclopropyl, —CH 2 OR 13 , or —CH 2 SR 14 ;

R 13 is H or C 1 -C 3 alkyl; and

R 14 is C 1 -C 3 alkyl.

8. The compound of claim 1 having the Formula (IA)

or a pharmaceutically acceptable salt thereof, wherein

R 3a is halo, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 fluoroalkyl;

R 3b is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, C 3 -C 6 cycloalkyl, or C 1 -C 3 fluoroalkyl;

R 3c is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, C 3 -C 6 cycloalkyl, or C 1 -C 3 fluoroalkyl;

A is selected from the group consisting of

(a)

 wherein

Y is —CH 2 —;

R 11 and R 12 are independently H or F; and

n is 1 or 2;

n′ is 0 or 1; or

(b)

 wherein

R a and R b are independently H or C 1 -C 4 alkyl; and

Q is —C(O)— or

R c is H, C 1 -C 3 alkyl, cyclopropyl, —CH 2 OR 13 , or —CH 2 SR 14 ;

 R 13 is H or C 1 -C 3 alkyl; and

 R 14 is C 1 -C 3 alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein no more than one of R 3a , R 3b , and R 3c is C 3 -C 6 cycloalkyl.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3c are both methyl, and R 3b is H.

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

12. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein A is

wherein

R a and R b are independently H or C 1 -C 4 alkyl; and

Q is —C(O)— or

R c is H, C 1 -C 3 alkyl, cyclopropyl, —CH 2 OR 13 , or —CH 2 SR 14 ,

R 13 is H or C 1 -C 3 alkyl; and

R 14 is C 1 -C 3 alkyl.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein

R a and R b are both H;

Q is

R c is H or —CH 2 OR 13 , and R 13 is C 1 -C 3 alkyl.

14. The compound of claim 1 selected from the group consisting of:

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-cyclopropylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(1-methylethyl)pyridin-2-yl]amino}pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4-chloro-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-chloro-4-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4,6-dichloropyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-{[2-aminopropyl]amino}-3-{[6-(trifluoromethyl)pyridin-2-yl]amino}pyridine-2-carboxamide;

rel-5-{[(1S,6S)-6-amino-2,2-difluorocyclohexyl]amino}-3-{[6-(trifluoromethyl)pyridin-2-yl]amino}pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5-methoxy-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-{[2-aminopropyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-methyl-4-(1-methylethoxy)pyridin-2-yl]amino}pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4-methoxy-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-methyl-5-(propan-2-yloxy)pyridin-2-yl]amino}pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(trifluoromethyl)pyridin-2-yl]amino}pyridine-2-carboxamide;

5-{[2-amino-3-methoxypropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-amino-3-ethoxypropyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-{[2-amino-3-methoxypropyl]amino}-3-{[6-(trifluoromethyl)pyridin-2-yl]amino}pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-fluoropyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-methoxypyridin-2-yl)amino]pyridine-2-carboxamide;

N 2 -{6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}-leucinamide;

5-{[2-aminopropyl]amino}-3-[(5-bromo-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-{[2-amino-3-(methylsulfanyl)propyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-{[1-(aminomethyl)propyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide;

N 2 -{6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}leucinamide;

5-{[2-amino-3-methoxypropyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5-fluoro-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1S,6S)-6-amino-2,2-difluorocyclohexyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

rel-5-{[(1S,6S)-6-amino-2,2-difluorocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-amino-1-methylethyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-amino-2-cyclopropylethyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-aminoethyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

N 2 -{6-carbamoyl-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}-leucinamide;

rel-5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[4-(1-hydroxy-1-methylethyl)-6-methylpyridin-2-yl]amino}pyridine-2-carboxamide;

5-[(2-amino-1,1-dimethylethyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(1-carbamoyl-2-methylpropyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-amino-1-methyl-2-oxoethyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-aminoethyl)amino]-3-[(6-methylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-{[2-amino-3-methoxypropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

5-[(2-amino-3,3-difluoropropyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide; and

5-[(2-amino-3-hydroxypropyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. The compound of claim 1 wherein the compound is 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof.